Quaternary ammonium addition salts of penicillin esters



ite States Patent 9 QUATERNARY AMMONIUM ADDITIQN SALTS F PENICILLIN ESTERS Erliug Knud Frederikseu, Holte, and Erling Juhl Nielsen, Chariottenlund, Denmark, assignors to Lpveus kemiske Fabrilr ved A. Kongsted, Copenhagen, Denmark, a firm N0 Drawing. Application November 27, 1951, Serial No. 258,515

This invention relates to quaternary ammonium addition salts of penicillin esters and to injectable and other compositions comprising particles of said salts in suspension in a suitable carrier.

This application is a continuation-in-part of our copending application Serial No. 168,384, filed June 15, 1950, now abandoned.

An object of this invention is to provide a series of novel quaternary ammonium salts of penicillin esters possessing advantageous antibiotic properties.

A further object of this invention is to provide a series of novel quaternary ammonium addition salts of penicillin esters by the use of which penicillin accumulates in various body tissues and fluids. Such accumulation provides a high concentration of penicillin which is effective therapeutically in the treatment of the infected portion of the body. The compounds may, furthermore, be advantageous in the treatment of patients who cannot stand the action of metal salts (certain heart diseases) and who cannot, therefore, stand treatment with, for instance sodium penicillin.

Another object of the invention is to provide for a composition comprising solid particles of our novel quaternary salts in suspension in a vegetable, animal or mineral oil, fat or wax to which a small amount, say 1-3 per cent, of a basic salt of aluminium and a fatty acid, such as stearic acid, may be added.

Further objects of the invention will appear from the following, where a more detailed description of our invention is given together with results of clinical tests, and further the invention is illustrated by examples showing a convenient method of preparing said compounds, but we wish it to be understood that our invention is not to be considered limited thereby.

Some of the quaternary salts are easily soluble in water and form crystals, while others form amorphous bodies, but in either case the salts have a full antibactelrlial effect corresponding to that of the content of peni- C1 in.

The compounds of the present invention are quaternary ammonium addition salts of penicillin esters represente y the follo ng f r ula:

1 33 where Pen.COO is the acyloxy residue of penicillin; where R is an alkylene bridge of 2 to 8 carbon atoms in which there are attached to the carbon atoms thereof, in addition to Pen.COO and N, radicals selected from the group consisting of hydrogen and alkyl groups, the total carbon atoms in R not exceeding 14; where R1 and R2 are selected from the group consisting of alkyl groups containing from 2 to 12 carbon atoms, provided that one of them does not exceed 3 carbon atoms, and radicals which together with the nitrogen atom form parts of a 5- to 6- membered ring, in which the other members are selected from the group consisting of CH2, CH, N, NR4, Q and S in a monocyclic radical, R4 being an alkyl group containing 1 to 2 carbon atoms, and the same in a dicyclic radical, provided that two adjacent C-atgms form part 2,694,063 Fatented Nov. 9, 1954 of a phenyl ring; Where R3 is an alkyl group containing from 1 to 3 carbon atoms; and where Y is an acid residue selected from the group consisting of hydrochloric, hydrobromic, hydroiodic, sulfuric, benzenesulfonic and toluenesulfonic acid residues.

Generally the total number of carbon atoms in R, R1 and R2 will not exceed 28, and in most instances it will be preferred to limit the alkylene bridge (R) to having 2 to 4 carbon atoms, the total number of carbon atoms in R not exceeding 9, with a total of carbon atoms in R, R1 and R2 not in excess of l8.

The preferred compounds of the invention are those with an unsubstituted alkylene bridge having 2 to 3 carbon atomsfwhere R1 is an alkyl group having from 1 to 12 carbon atoms; and where R2 and R3 are alkyl groups having from 1 to 4 carbon atoms, Y being any of the above acid residues.

It has been noted that in the case of R being an alkylene bridge of 2 to 3 carbon atoms; R1, R2 and R3 being alkyl groups having from 1 to 3 carbon atoms; and Y being an acid residue as defined above, particularly desirable results have been obtained in respect of accumulation in the liver tissue.

It is to be understood that in the compounds of the invention, R1, R2 and R3 may be the same or different, or two of them may be the same and the third dilferent.

Further, it will be noted that in the above formula the above bridges are connected at the left with the acyloxy residue of the penicillin and at the right with the nitrogen atom; thus the carbon atom at the left of the ethylene bridge is designated as 2 and the one at the right as 1; Whereas in the octylene bridge the carbon atoms reading ,fromleft to right are designated 8, 7, 2, 1, respectively, and the same is true of the other bridges.

While the preferred compounds will be the quaternary ammonium addition salts of the esters of benzylpenicillin (penicillin G) and such compounds will be more specifically referred to herein, the penicillin residue in the compound may, if desired, be that of any other penicillin, for example, penicillin O, K, F, dihydro-F and X, as Well as mixtures of various penicillins, for example, a mixture obtained by submerged cultivation.

Typical compounds of the invention are those in which the bridge is ethylene propylene, butylene, pentylene, hexylene, heptylene or octylene, either unsubstituted or containing substituents as defined in the formula, where the t tal carbon atoms in R do not exceed 14, for example, methylethylene, dihexylethylene, methyloctylene or i-n-propyloctylene; those in which R1 and R2 are alkyl groups varying from methyl to dodecyl, for example, dimethyl, butyloctyl, di-dodecyl; and those in which R1 and R2 together with the nitrogen atom form monoand dicyclic radicals, for example, piperidino; alkyl substituted piperidino, where the total of carbon atoms in the substituents does not exceed 14, such as dimethylpiperidino. tetramethyloiperidino, hexyloiperidino and butylethylpiperidino: N-methyl and N-ethyl substituted piper: azino; pyrrolidino; morpholino; imidazolino; thiazolidino: tetrahydroquin lino and -isoquinolino; isindolino; indolino; and oxazolidinn. Advantage usly, in the case of heterocycles, the ring will be a piperidine ring, an alkyl substituted piperidinering or pyrollidine ring, where the substituents are methyl or ethyl and do not exceed 4, a morpholine ring of a N-methylor N-ethyl-pirerazine ring.

While the preferred esters will be the esters of benzyl penicillin (penicillin G) and such esters will be more specifically referred to herein, the penicillin residue in the compound may. if desired, be that of any other penicillin O, K, F, dihydro-F and X as well as mixtures of various penicillins, for example a mixture obtained by submerged cultivation.

Typical compounds of the present invention are the quaternary amm nium addition salts of the aminoalcohcl esters of pe icillin described and claimed in our co-pending applications. Serial Nos. 258,511, filed November 27, 1951:. and 258.514, filed November 27, 1951. The method of producing such esters is described and claimed in our co-pendimz application, Serial No. 258,513, filed November 27, 1951. Y

In producing the quaternary ammonium addition salts, the free penicillin ester is dissolved in a suitable organic solvent. such as benzene, ethanol or ether, and a suitable alkylating agent, such as an alkyl halide, for example ethyl chloride, a dialkyl sulfate, for example diniethyl sulfate, or an alkyl ester of benzeneor toluenesulphonic acid, for example the methyl ester, is added. The solvent is then removed, preferably by distillation in vacuo, whereby the quaternary salt is obtained and may be used as it is or re-crystallized.

The quaternizing process is illustrated by the following scheme of reaction:

CH3 /CH3 B-CzH;-N +omo1 permit-enter CH3 CH3 Blood Liver Ratio. units units Liver/Blood Quaternary salt l4. 4 17. 6 1. 22 Sodium salt 29. 8 10. 4 O. 35

It will be noted that the accumulation in the liver of the quaternary salt is about four times that of sodium penicillin.

We have found that by suspending our new quaternary ammonium additiori'ssalts of the amino esters of penicillin in a vegetable or animal oil in which is dissolved a quaternary, for Example 1 to 3 per cent, of a salt of aluminium, and a lipophilic acid, particularly a basic salt, such as aluminum monostearate or aluminium distearate, we can obtain compositions having a more enduring protracted effect than that obtained by injection of said salts suspended in saline.

Instead of stearates other salts of fatty acids having 12 to 22 carbon atoms in the molecule may be used. Examples of a suitable vegetable oil are peanut oil, cottonseed oil, soya oil, sesame oil and olive oil.

In the following, examples are given of the production of the novel compounds of the invention.

EXAMPLE 1 Quaternary ammonium addition salt of benzylpenicillin- B-diethylaminoethylester and ethyl iodide EXAMPLE 2 Quaternary ammonium addition salt of benzylpenicillinfl-dimethylaminoethyl ester and dimethyl sulfate The hydrochloride of benzylpenicillin-dimethylaminoethyl ester is dissolved in water and one equivalent of sodium hydroxide solution is added. The free penicillin ester is then isolated by extraction with ether and the solution is dried over sodium sulfate. The solvent is then removed by distillation in vacuum.

The free penicillin ester is dissolved in alcohol and dimethyl sulfate is added to the solution. The solution is allowed to stand at room temperature or is heated to a suitable temperature to bring about interaction between the free penicillin ester and the dimethyl sulfate, with the resulting formation of the desired quaternary salt. The solvent is removed by distillation in vacuo and the residue is crystallized from a suitable solvent or used as such.

4 EXAMPLE 3 Quaternary ammonium addition salt of benzylpenicillin- B dimethylamino 5 methylethyl ester and propyl chloride The free penicillin ester is dissolved in alcohol and propyl chloride is added to the solution. The solution is allowed to stand at room temperature or is heated to a suitable temperature to bring about interaction between the free penicillin ester and the propyl chloride, with the resulting formation of the desired quaternary salt. The solvent is removed by distillation in vacuo and the residue is crystallized from a suitable solvent or used as such.

EXAMPLE 4 Quaternary ammonium addition salt of benzylpenicillin-piperidinoethyl ester and methyl iodide EXAMPLE 5 Quaternary ammonium addition salt 0 benzylpenicillinfi-(4-morpholino)-ethyl ester and dimethyl sulfate This compound is prepared in accordance with the procedure of Example 4.

We claim:

1. Quaternary ammonium addition salts of penicillin esters represented by the following formula:

where Pen.COO represents pencillin with the hydrogen atom removed from the carboxyl group, R is an unsubstituted alkylene of 2 to 3 carbon atoms, R1 is an alkyl group having from 1 to 12 carbon atoms and R2 is an alkyl group having from 1 to 4 carbon atoms, and radicals which together with the nitrogen form a heterocyclic group selected from the group consisting of a piperidine ring, an alkyl substituted piperidine ring and an alkyl substituted pyrrolidine ring where the alkyl substituents do not exceed 4 and are alkyl of l to 2 carbon atoms, a morpholine ring, and an N-alkyl piperazine ring where the alkyl is of l to 2 carbon atoms, Ra is alkyl of from 1 to 4 carbon atoms, and Y is an acid anion selected from the group consisting of hydrochloric, hydrobromic, hydriodic, sulfuric, benzene-sulfonic and toluene sulfonic acid anions.

2. Quaternary ammonium addition salts of penicillin esters represented by the following formula where PenCOO represents penicillin with the hydrogen atom removed from the carboxyl group, R is unsubstituted alkylene of from 2 to 3 carbons, R1 is an alkyl group of from 1 to 12 carbon atoms, R2 and R3 are alkyl groups of from 1 to 4 carbon atoms, and Y is iodine.

3. Products as set forth in claim 2 in which Pen.COO is the acyloxy residue of benzyl penicillin.

4. The quaternary ammonium addition salt of benzylpenicillin-gS-diethylaminoethylester and ethyl iodide.

5. The quaternary ammonium addition salt of benzylpenicillin-fi-dimethylaminoethyl ester and dimethyl sulfate.

6. The quaternarv ammonium addition salt of benzylpenicillin-e-dimethylamino-fi-methylethyl ester and propyl chloride.

7. The quaternary ammonium addition salt of benzylpenicillin-piperidinoethyl ester and methyl iodide.

8. The ouaternarv ammonium addition salt of benzyl- PCI'ElCllllIl-fi-(l-IBOIPhOllHO)-ethyl. ester and dimethyl sui ate.

(References on following page) References Cited in the file of this patent Number UNITED STATES PATENTS Name Viaud McDufiie et a1 Dec.

ate

OTHER REFERENCES ci'genter: J. Am. Chem. Soc., vol. 70 (1948), pp.

Kirchner et a1.: J. Org. Chem, vol. 14, May 1949, 

1. QUATERNARY AMMONIUM ADDITION SALTS OF PENCILLIN ESTERS REPRESENTED BY THE FOLLOWING FORMULA: 